Sex differences in cyclosporine pharmacokinetics and abcb1 gene expression in mononuclear blood cells in african american and caucasian renal transplant recipients

摘要

Cyclosporine exhibits pharmacokinetic and pharmacodynamic variability in renal transplant recipients (RTR) attributed to P-glycoprotein (P-gp), anABCB1 efflux transporter that influences bioavailability and intracellular distribution. Data on race and sex influences on P-gp in RTR are lacking. Weinvestigated sex and race influences on cyclosporine pharmacokinetics and ABCB1 gene expression in peripheral blood mononuclear cells (PBMC). Fiftyfourfemale and male African American and Caucasian stable RTR receiving cyclosporine and mycophenolic acid completed a 12-hour study. ABCB1 gene expression was assessed in PBMCs pre-dose and 4 hours after cyclosporine. Statistical analysis used mixed effects models on transformed, normalizedABCB1 expression and cyclosporine pharmacokinetics. Sex and race differences were observed for the dose-normalized area under the concentrationcurve (AUC0-12/Dose) [P =.0004], apparent clearance [P =.0004] and clearance/body mass index (CL/BMI) [P =.027] with slowest clearance andgreatest drug exposure in females. Sex and race differences were found pre-dose and 4 hours for ABCB1 [P < .0001] with females having less expressionthan males. ABCB1 differences were observed between pre-dose and 4 hours [P =.0009]. Female RTR had slower cyclosporine clearance and lowerABCB1 gene expression in PBMC suggesting reduced efflux activity and greater intracellular drug exposure.